Since CHRNA2 and other nicotine receptor genes that have been identified as risk loci for nicotine dependence and smoking behavior27,30, the potential confounding from smoking was evaluated carefully, and all our approaches supported that the results reflect CUD without strong confounding from smoking. Furthermore our results suggested that the identified CUD risk locus, which is also genome-wide significantly associated with smoking30 however with significant lower effect size than observed for CUD, has a pleiotropic effect on both smoking and CUD in the general population, with greatest impact on CUD risk. Additionally a recent GWAS of lung cancer identified a genome-wide significant locus just upstream CHRNA243. This locus is LD distinct from the locus identified in the present study, but the risk allele was also found to be associated with decreased CHRNA2 expression in cerebellum. In analyses of smoking behavior, the lung cancer risk allele, was reported nominally associated with smoking and age of initiation43. This result is in line with our observation of the CUD risk variant, and thus decreased CHRNA2 expression, being associated with younger age at first diagnosis of CUD.
